Cell replacement and visual restoration by retinal sheet transplants

Abstract

Retinal diseases such as age-related macular degeneration (ARMD) and retinitis pigmentosa (RP) affect millions of people. Replacing lost cells with new cells that connect with the still functional part of the host retina might repair a degenerating retina and restore eyesight to an unknown extent. A unique model, subretinal transplantation of freshly dissected sheets of fetal-derived retinal progenitor cells, combined with its retinal pigment epithelium (RPE), has demonstrated successful results in both animals and humans. Most other approaches are restricted to rescue endogenous retinal cells of the recipient in earlier disease stages by a ‘nursing’ role of the implanted cells and are not aimed at neural retinal cell replacement. Sheet transplants restore lost visual responses in several retinal degeneration models in the superior colliculus (SC) corresponding to the location of the transplant in the retina. They do not simply preserve visual performance – they increase visual responsiveness to light. Restoration of visual responses in the SC can be directly traced to neural cells in the transplant, demonstrating that synaptic connections between transplant and host contribute to the visual improvement. Transplant processes invade the inner plexiform layer of the host retina and form synapses with presumable host cells. In a Phase II trial of RP and ARMD patients, transplants of retina together with its RPE improved visual acuity. In summary, retinal progenitor sheet transplantation provides an excellent model to answer questions about how to repair and restore function of a degenerating retina. Supply of fetal donor tissue will always be limited but the model can set a standard and provide an informative base for optimal cell replacement therapies such as embryonic stem cell (ESC)-derived therapy.

Characterization of Three-Dimensional Retinal Tissue Derived from Human Embryonic Stem Cells in Adherent Monolayer Cultures

“…Transplanted dissociated cells may not survive long term in such abnormal conditions [10]. The survival of transplanted PRs is especially challenging if the recipient retina lacks a functional RPE [11]. These considerations lead to the conclusion that grafting retinal tissue (such as embryonic retina) rather than dissociated PRs may be more effective for repairing the retina [12] in patients suffering from advanced retinal degeneration.…”

Stem cell therapies for retinal diseases: recapitulating development to replace degenerated cells

“…RPE cells injected in a cell suspension, as in the ongoing Asteallas trial, might be able to reestablish function, whereas other groups are using patches of previously polarized RPE cells (Falkner-Radler et al, 2011;Seiler and Aramant, 2012). Inserting a patch requires a larger cut in the retina, which can cause additional complications, and as it is a foreign agent, the substrate itself may cause complications.…”

Central Nervous System

“…The main issue that RPE transplantation faces is that if photoreceptor degeneration has occurred, just replacing the RPE will not reestablish vision as functional photoreceptors are also needed [182]. Therefore, RPE transplantations must be performed early in disease progression, preferably at the dry AMD stage, before photoreceptor degeneration begins.…”